It is well known that many natural products contain one or more asymmetric centers and thus can occur in optically active forms. As a rule, one optical form predominates in nature, and only this optical isomer is responsible for the particular properties of the compound such as taste, odor, toxicity and pharmacological properties. This generally applies as well to synthetic compounds, particularly in the medicinal or pharmaceutical field. That is, one optical antipode usually exhibits the desired biological activity, whereas the other does not or does to a much smaller extent or, in fact, may even exhibit undesirable properties.
It has become accepted procedure in the synthesis of biologically active molecules to prepare the desired molecule in optically active form. While, in some cases, this may be accomplished utilizing enzymatic or fermentation techniques, a chemical optical resolution is the only method which can usually be used on a technical scale. For convenience, resolution is usually performed at a stage in which the intermediate or final product has a functional group which is suited for the resolution process, usually an amine or carboxylic acid group. The racemic compound to be resolved is reacted with an optically pure compound having a complementary functional group to form mixtures of diastereomeric compounds, usually salts, which may then be separated due to their differences in physical properties. Usually fractional crystallization is employed. Compounds having a carboxylic acid group are commonly resolved by reaction with an optically active amine, and compounds possessing an amine group may be resolved by reaction with an optically active acid, for example, an optically active carboxylic or sulfonic acid.
In the past, the resolution of racemates having carboxylic acid groups was accomplished utilizing optically active amines derived from natural sources, most notably the alkaloids such as brucine, strychnine, cinchonidine, and so forth. The use of these compounds presents many disadvantages such as toxicity, questionable optical purity, availability (inasmuch as they must be obtained from natural sources), and the fact that they normally occur in nature in only one optical form so that only one antipode is available for a potential resolution problem.
In recent years, the use of simpler synthetic organic amine resolving agents has become wide-spread. In particular, amines that have been used extensively for optical resolution are antipodes of .alpha.-methylbenzylamine (.alpha.-phenylethylamine) and simple derivatives thereof, such as N- and N,N-lower alkyl derivatives; as well as antipodes of .alpha.-naphthylethylamine. While these amines have been used extensively, there are many instances in which resolution does not occur either through the lack of formation of crystalline salts or the fact that the diastereomeric salts formed, even if crystalline, often do not differ sufficiently in physical properties to allow facile separation.
Hence, it would be desirable to have available optically active amine resolving agents which are easily prepared, are simple to use, provide highly crystalline salts, and which will resolve a wide range of racemic acids of varying structure and type.
Both optical antipodes of .alpha.-methyl-p-nitrobenzylamine p-nitrobenzylamine have been previously described in the literature. See for example, Cope, et al., Journal of the American Chemical Society, Vol. 92, page 1243 (1970). The antipodes of this compound have been used, as complexes with platinum, for the partial resolution of a cylic allene, notably 1,2-cyclononadiene. However, there was no suggestion to use such compounds for the resolution of organic carboxylic acids.